Chronic obstructive pulmonary disease (COPD) is a complex disease of substantial public health concern, and is the 4th leading cause of mortality globally, with morbidity and mortality expected to worsen by the year 2020. Tobacco use is a major environmental risk factor in the development of COPD;however, only 10-20% of smokers develop symptomatic disease. Animal and human studies provide support for the role of genetic factors for both smoking behavior and its associated outcomes, including lung function and other manifestations of COPD, yet only a small proportion of potentially causal genes have been identified. The Lung Health Study (LHS), a 14.5-year, multicenter, randomized clinical trial aimed to determine whether a program of smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in pulmonary function or alter COPD mortality, represents one of the largest COPD cohorts worldwide (N=5,887). As part of a previous NHLBI-funded study, we developed a DNA repository including >4,800 LHS participants. We plan to perform a genome-wide association study (GWAS) for COPD and associated quantitative traits in this well-characterized cohort and use existing GWAS datasets to validate our findings. Because we also hypothesize that some genes may contribute to nicotine addiction and thus tobacco use (the strongest environmental risk factor in COPD), we will test for association between genetic markers and this outcome, and will similarly validate those findings, and test for gene-environment interaction. A major strength of our application is the collaborative effort with colleagues at the James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research in Vancouver, and the LHS Data Coordinating Center at the University of Minnesota. Additional collaborations with investigators conducting GWAS in relevant datasets include those from Harvard University (the Framingham Health Study, the National Emphysema Treatment Trial/Normative Aging Study), University of Washington (the Cardiovascular Health Study), University of North Carolina (Tobacco and Genetics Network), and University of Toronto (Smoking Treatment for Ontario Patients Study). Goals of this study are: (1) to perform GWAS in European American and African American LHS subjects using a genome-wide array of 550,000 SNPs, with individual rate of decline of lung function and COPD susceptibility as the primary outcome phenotypes;(2) to cross-validate significant associations using existing GWAS data in independent populations;(3) to test for gene-environment interactions using markers associated with COPD outcomes, with a particular focus on tobacco use;and (4) to perform tests for association between the markers and outcomes reflecting nicotine addiction (e.g. sustained quitters vs. continuous smokers), and to validate significant associations in a replicate population. Findings from this study will provide a better understanding of the complex pathways related to risk of COPD and its associated phenotypes.